Maria Schubert

Survival in Patients with High-Risk Prostate Cancer Is Predicted by miR-221, Which Regulates Proliferation, Apoptosis, and Invasion of Prostate Cancer Cells by Inhibiting IRF2 and SOCS3

A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high-risk prostate cancer, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness, and apoptosis in prostate cancer at least partially via STAT1/STAT3-mediated activation of the JAK/STAT signaling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signaling pathway. miR-221 expression sensitized prostate cancer cells for IFN-γ-mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk prostate cancer.

Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer

Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.

Outcome Predictors of Radical Prostatectomy Followed by Adjuvant Androgen Deprivation in Patients with Clinical High Risk Prostate Cancer and pT3 Surgical Margin Positive Disease

PURPOSE Patients with high risk prostate cancer with pT3 tumor and positive surgical margins have a high risk of biochemical failure after radical prostatectomy and adjuvant androgen deprivation therapy. Predictors of cancer related death in this patient group are necessary. MATERIALS AND METHODS We performed subset analysis of a prospective trial including 550 consecutive patients with preoperative high risk prostate cancer (prostate specific antigen greater than 20 ng/ml ± cT3/4 ± biopsy Gleason 8-10). Men who underwent radical prostatectomy and received continuous adjuvant androgen deprivation therapy for pT3a/b N0-1 positive surgical margin disease were included in the analysis, and none of the patients received neoadjuvant androgen deprivation therapy or adjuvant radiation therapy. RESULTS Overall 173 of 550 patients (31.5%) with a median followup of 67 months met the study inclusion criteria. For these men the estimated 8-year prostate cancer specific and overall survival rates were 86.3% and 77.0%, respectively. Tumor stage and positive surgical margin at the bladder neck were independent predictors of prostate cancer specific survival and overall survival, and were used to substratify cases. Those with pT3b disease with positive surgical margins at the bladder neck had the highest risk of death (5-year cancer specific survival 60.0% and overall survival 52.3%), while pT3a disease (regardless of positive surgical margin location and lymph node invasion) and pT3b tumors with negative bladder neck margins had 8-year prostate cancer specific survival and overall survival rates of 92.0% and 84.9%, respectively. CONCLUSIONS The results of this trial demonstrated the heterogeneity of high risk prostate cancer cases with T3 tumors and positive surgical margins. The presented substratification by tumor stage and positive surgical margin location identifies men at high risk for prostate cancer related death and might help in the design of adjuvant therapy trials.

The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis

Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n = 86) or no adjuvant ADT (group 2, n = 86). Results. Only 11.6% of the patients died, 2.3% PCa related. Estimated 5–10-year clinical progression-free survival was 96.9% (94.3%) for group 1 and 73.7% (67.0%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.

Lower urinary tract symptoms (LUTS)

Symptome des unteren Harntrakts, die wahrend der Blasenfullung bzw. Entleerung bei alteren Mannern auftreten konnen, werden unter dem Uberbegriff LUTS zusammengefasst. Traditionell wurden bestehende Beschwerden einer vergroserten Prostata zugeordnet, was jedoch in den letzten Jahren zunehmend hinterfragt wurde Man geht heutzutage eher von einer multifaktoriellen Atiologie im Hinblick auf die Beschwerden des unteren Harntrakts aus. Patienten, die sich mit LUTS vorstellen, zeigen haufig mehr mehrerer Komponenten einzelner Entitaten wie des benignen Prostatasyndroms, der benignen Prostata-Obstruktion, der benignen Prostata-Vergroserung, der uberaktiven Blase und mehreren weiteren Entitaten. Die hochste Inzidenz dieser unterschiedlichen Entitaten hat das benigne Prostata-Syndrom (BPS), bei dem sich eine Vergroserung der inneren periurethralen Drusen findet, und das eine Verengung der prostatischen Harnrohre verursacht.